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MODERN CLASSICS (Number 1)
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Regional distribution
of gas in the lung
Joseph Milic-Emili CM MD FRSC
Meakins-Christie Laboratories, McGill University, Montreal, Quebec
J Milic-Emili. Regional distribution of gas in the lung.
Can Respir J 2000;7(1):71-76.
Distribution pulmonaire régionale des gaz
RÉSUMÉ : En 1966, un article intitulé «Regional distribution of gas in the lung» a été publié dans le Journal of Applied
Physiology et est devenu l’un des 100 articles les plus souvent cités en recherche clinique entre 1961 et 1978. Son auteur vénérable nous présente ici l’historique et l’état des
connaissances scientifiques à l’époque de sa publication et il
passe en revue les principales conclusions de l’article et les
développement qui en ont découlé.
In 1966, a paper entitled “Regional distribution of gas in the
lung” was published in the Journal of Applied Physiology
and became one of the 100 most-cited papers of clinical research from 1961 to 1978. The senior author provides the
background and state-of-the art at the time of its publication,
and reviews the main findings of the paper and subsequent
developments.
Key Words: Closing volume; Elastic properties; Lung; Regional
pleural pressure
Wonder, rather than doubt, is the root of knowledge.
Professor Rodolfo Margaria, both of which, at the time, were
devoted to research in exercise physiology. My introduction
to respiratory mechanics began in 1957 when a very capable
Belgian physiologist, Jean-Marie Petit, came, through a misunderstanding, to our department to learn how to measure
esophageal pressure. Such measurements had not been done
in Milan, nor was there any suitable equipment available.
Nevertheless, using a water manometer, we produced an important paper on the measurement of esophageal pressure (6).
Dr Petit, who was one of the best experimental physiologists
that I have ever known, invited me to join him in his laboratories in Liège, Belgium, which were well equipped for studies
in respiratory mechanics, and together we produced a large
series of papers in this field. Thus, I became an expert in respiratory mechanics through a fortuitous misunderstanding.
Boston: From 1960 to 1963, I was a research fellow at the
Abraham Heschel
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he 1966 paper entitled “Regional distribution of gas in
the lung” (1) became one of the 100 most-cited papers of
clinical research from 1961 to 1978 (2). It inspired many investigations and provided the kernel for understanding regional lung function (3,4). It also played an important role in
propelling me to become one of the 1,000 most-cited authors
from 1965 to 1978 (5). Before this study, my research training
in Milan, Liège and Boston was essentially ‘programmed’ to
allow me to formulate concisely the basic factors determining
the regional distribution of gas in the lung.
Milan and Liège: From 1956 to 1959, I worked at the Department of Physiology at the University of Milan, Italy with
Correspondence: Dr Joseph Milic-Emili, Meakins-Christie Laboratories, McGill University, 3626 St Urbain Street, Montreal, Quebec H2X
2P2. Telephone 514-398-3864 ext 2990, fax 514-398-7483, e-mail [email protected]
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Harvard School of Public Health, Boston, where, under the
guidance of Dr Jere Mead, I published two papers dealing
with the static volume-pressure (V-P) relationship of the
lung and the topography of pleural surface pressure (7,8).
With the above research background, the solution to the factors governing regional lung function was inevitable, perhaps even pedestrian, as shown below.
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BACKGROUND
Before 1966, studies with inert gases, differential lobar
bronchospirometry and, more recently, with radioactive gas
methods using external counters showed that ventilation in
the normal human lung was uneven and that this unevenness had a topographical distribution (3,4). However, the
mechanisms determining this unevenness were poorly understood. Retrospectively, this is surprising because the essential elements governing the regional distribution of gas
in the lung were known. Indeed, it had been known since
1961 that there is a vertical gradient in pleural pressure of
about 0.2 cm H2O/cm descent in the lung (9), and my own
work at the Harvard School of Public Health supported these
results (8). At the same institution, based on experiments on
excised pulmonary lobes of dogs, Frank (10) concluded that,
at least at a lobar level, the static mechanical properties of the
lung are relatively uniform. That is, the static V-P relationships of the various lobes are essentially the same, provided
that volumes are expressed as a percentage of the total lobar
volume measured at the same distending pressure. Although the evidence was less certain, the consensus at the
Harvard School of Public Health at that time was that the intrinsic elastic properties were probably isotropic, also at a
gross sublobar level. This implied that regional static V-P relations, normalized for regional total lung capacity (TLCr),
were similar to the overall static V-P curve of the lung, normalized for overall total lung capacity (TLC). Accordingly,
the overall static V-P curve of the lung (V, %TLC) obtained
with the esophageal balloon method (7) also pertains to different lung regions (regional lung volume [Vr], %TLCr),
as shown in the top panel of Figure 1. The middle panel of
Figure 1 depicts the regional distribution of static transpulmonary pressure (Pr) at functional residual capacity
(FRC): Pr decreases by about 0.2 cm H2O/cm descent
down the lung (8,9). Based on this information, it is possible to compute the regional lung expansion (Vr, %TLCr) as
a function of vertical distance (D) down the lung (bottom
panel of Figure 1). Indeed, at a distance of 5 cm from lung
top, Pr at FRC is 7.6 cm H2O, as indicated by point A in the
middle panel of Figure 1. This corresponds to a Vr of 63%
TLCr, as indicated by point A in the top panel. This volume is
next plotted against a D of 5 cm in the middle panel. Using a
similar approach (eg, points B and C), it is possible to
compute the regional volume expansion over the entire distance down the lung (solid line). Because the relationships in
Figure 1 pertain to FRC, the middle panel represents the regional distribution of FRC (FRCr) down the lung, while the
vertical distance from the FRCr line to the upper abscissa
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Figure 1) Top Regional static volume-pressure relationship of the
lung, which is assumed to be isotropic. Regional and overall lung
volume are expressed respectively as a percentage of regional total
lung capacity (TLCr) and overall total lung capacity (TLC). Middle
Regional transpulmonary pressure at different vertical distance (D)
down the lung at functional residual capacity (FRC). Bottom Regional lung volume (Vr) (%TLCr) as a function of D. The letters A,
B and C indicate how the regional FRCr in the bottom panel was
computed from the corresponding relations in the other panels. For
further information, see text. Adapted from reference 1. ICr
Regional inspiratory capacity; V Volume; Pr Transpulmonary
pressure
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(which equals 100% TLCr) reflects the regional inspiratory
capacity (ICr).
Although the regional distribution of gas at different
vertical levels of the lung could have been predicted before our 1966 study (1), it had not been done. In this regard, I will note that the nature and magnitude of the
vertical pleural pressure gradient down the lung, as well
as the problem of homogeneity and nonhomogeneity of
regional lung mechanics, were topics that were hotly discussed at many seminars held at the Harvard School of
Public Health. Nevertheless, the basically straightforward step of predicting the regional distribution of gas
based on the available information had not been
attempted. This reinforces my opinion that seminars are
an excellent vehicle to improve scientific reasoning and
background knowledge, but seldom provide important
scientific breakthroughs.
Montreal: In 1963, I was invited by David V Bates to come
to McGill University, Montreal, Quebec. His group had introduced a quantitative method for assessing regional pulmonary function using 133Xenon (11). Their paper, which was
also among the 100 most-cited articles of clinical research
(1961 to 1978), provided a quantitative method to study regional lung function.
My arrival to Canada was somewhat hectic because I was
asked by Canadian immigration to provide a chest x-ray. This
showed that I had overt tuberculosis! Nevertheless, I was
allowed to come to Canada on a special minister’s permit,
thanks to strenuous efforts by Drs David Bates and Maurice
McGregor. I am very grateful because I have spent a very
happy time at McGill University. Unknown to me at that
time, in view of my background training, I was ready to make
a rapid breakthrough at McGill in the area of regional lung
function.
I arrived to Montreal in the middle of the summer of 1963,
at a time when all the staff were on vacation. I was put in a
small office with a single reprint on my desk, that of Ball et
al (11). I proceeded to read it with interest, particularly as I
thought that the studies with radioactive gases were a new,
rather exotic area of research. On the fourth page of that paper were two equations that described the Xe133 method, and
which, at first, I could not understand. After a while, however, I realized that the method of Ball et al (11) was merely
an application of the gas dilution principle, with which one
could measure, for example, the FRCr at different levels
down the lung, ie, the missing link in Figure 1 (middle
panel). In fact, at that moment I realized the significance of
my previous research (6-8) in terms of regional lung expansion. For the first time in my life, I was now in full control of
a research line that rapidly led to the experimental verification of the analysis in Figure 1 and the development of the
‘onion skin diagram’ (Figure 2).
Peer review: The manuscript entitled “Regional distribution
of inspired gas in the lung” (1) was submitted for publication
to the Journal of Applied Physiology at the beginning of 1965,
together with three companion papers (12-14). The name of
Dr Bates does not appear in the primary paper because he told
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Figure 2) Regional lung volume (Vr), expressed as a percentage of
regional total lung capacity (TLCr). Abscissa: overall lung volume (V), expressed as percentage of total lung capacity (TLC)
below and as a percentage of vital capacity (VC) above. The broken line (line of identity) indicates the percentile degree of expansion of the regions equal to that for the entire lungs. The vertical
distance (D) from top of lungs (in cm) is indicated on each curve.
From reference 1. RV Residual volume; FRC Functional residual
capacity. Reproduced with permission from reference 1
me that, in view of the importance of the study, he wanted to
leave all the credit to me! Such generosity is seldom encountered. His name, however, appears on “Regional distribution of
ventilation and perfusion as a function of body position ”(13).
While the three companion papers received favourable reviews, this was not the case with reference 1, which was rejected! One of the two reviewers concluded the extensive
criticism with the following statement: “My comments should
be considered merely citations of examples of the faults in this
paper rather than an exhaustive catalog.” Among his long list
of faults he stated that “one of the serious problems of your
presentation was that you have used %TLC and %TLCr as
units of volume.” In fact, these units were pivotal for understanding the regional distribution of gas in the lung.
Clearly, this reviewer had more doubt than wonder.
Despite the adamant rejection of our paper, the section
editor, Dr Jere Mead, decided to accept it for publication. In
reference to this, I will add that one of the reviewers of the
companion paper entitled “Regional distribution of pulmonary perfusion in erect man” (12) wrote that “While reading
the manuscript I felt like listening to the music of Wagner.”
In his correspondence with us, Dr Mead stated that he accepted this paper on the assumption that the reviewer actually liked Wagner’s music!
WHAT WAS DISCOVERED
The 1966 paper provides a quantitative validation of the
factors governing the regional distribution of gas within
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airway closure in the dependent lung zones as residual volume is approached. Lung regions empty progressively with
decreasing lung volume until a minimal limiting volume is
reached. This limiting volume reflects gas trapping behind
closed small airways. These findings led to the concept and
measurement of the closing volume (17). Incidentally, that
paper was also originally rejected.
After publication, our paper became very popular immediately, stimulating a vast number of physiological and clinical investigations, which have been extensively reviewed
elsewhere (3,4,18,19). Furthermore, our main findings are
now described in most textbooks of respiratory physiology,
and have become part of the physiological heritage. It is axiomatic, however, that scientific diagrams, such as Figures 1
and 2, have limitations in view of the complexity of the respiratory system and the ‘scientific’ approach on which they are
based.
Broadly speaking, the approach to a given topic can be
‘mystic’ or ‘scientific’: perception of the whole versus selection of parts. Because ‘scientific’ accounts are by definition
selective, they provide only a partial story. As a result, all
‘scientific’ diagrams have limitations because they are necessarily based on simplifying assumptions. The limitations
of Figures 1 and 2 will become apparent below.
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Figure 3) Distribution of ventilation during quiet breathing in a
young (left) and in an old subject (right). In the old subject, at functional residual capacity (FRC) the pleural pressure is positive at the
lung base, causing airway collapse, so that ventilation is distributed
preferentially to the upper zones (see arrows). Note the loss in elastic recoil of the lungs in the old subject, ie, the static volumepressure curve is displaced to the left. Reproduced with permission
from reference 15
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KNOWLEDGE GAINED SINCE 1966
Since 1996, there has been considerable progress in the
understanding of regional lung function, as described elsewhere (3,4,18,19). This account will be limited mainly to a
review of the limitations of Figures 1 and 2, which pertain to
static or quasistatic conditions.
The regional distribution of gas depends on many factors,
which include: shape of the static V-P curve of the lung; regional differences in elastic properties of the lung; regional
changes in DPr, which can vary depending on the strength of
respiratory muscle contraction as well as type of contracting
muscle (eg, diaphragm versus external intercostal accessory
muscles); regional differences in flow resistance; and flow
rates.
In experimental animals and humans, the static V-P curve
of the lung appears to be exponential in character, a fact that
is consistent with nonsequential lung filling and emptying at
lung volumes greater than FRC (Figure 2) (1). However, in
most experimental animals, there are small but consistent
differences in elastic properties between the upper and lower
lung lobes (18,19). Although a study on normal excised human lung lobes suggested that such differences are not present in humans (20), studies with the single-breath washout
method at 1G (normal gravity) and during sustained microgravity (Spacelab SLS-1) suggest that, in humans, there are
also regional differences in elastic properties, which result in
some degree of sequential lung emptying at volumes greater
than FRC (21).
The question of whether the changes in DPr are regionally
uniform is of considerable theoretical and practical interest.
Indeed, apart from the implications on regional distribution
the lung, outlined in Figure 1. Furthermore, it introduced the
‘onion skin diagram’ depicted in Figure 2. This diagram was
derived from data collected from a seated, normal young man
after he had inhaled air labelled with Xe133. Regional count
rates over different parts of the chest were measured using
12 scintillation counters. This is another way of plotting the
information in the right upper panel of Figure 1, except that
regional volume is plotted against overall lung volume, and
the vertical distance down the lung is depicted by the different isopleths. Figure 3 depicts the distribution of ventilation
during quiet breathing in a normal young man (1), together
with that observed on an elderly normal man (15).
Progress in physiology is often marked by the development of diagrams that provide a concise formulation of basic aspects. In respiratory physiology, there are many
examples, such as the oxygen-carbon dioxide diagram of
Rahn and Fenn (16). Our study also provided such a diagram, namely the ‘onion skin diagram’ (Figure 2). For upright humans, Figure 2 indicates a number of things. The
alveoli in the upper lung regions are more expanded than
in the lower lung zones at all lung volumes, except at full
inflation (100% TLC). Above FRC there is nonsequential
lung filling. This is reflected by the linear relationships between regional and overall lung volume, with the ventilation per alveolus being higher in the lower lung zones,
reflected by the steeper slopes of the lines. Below FRC,
lung emptying is sequential, reflecting progressive small
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ing in the upright posture, the primary determinants of ventilatory inhomogeneity are not gravitational in origin.
Indeed, under these conditions, the overall distribution of
ventilation is only slightly less inhomogeneous in microgravity than at 1G (26). By contrast, transition from standing to supine position at 1G results in significantly
increased inhomogeneity of ventilation distribution.
Postscript: The 1966 article, although written in a clear
and concise fashion, is not easy to read, because it requires
considerable knowledge of both respiratory mechanics
and gas exchange. It still is, however, the essential synthesis of the factors that govern regional distribution of gas
in the lung. In preparing this manuscript, however, I found
that, at this time in my life, the names of my co-workers
have become more important to me than the scientific content of the paper. We had a good time! In particular, I wish
to acknowledge the major scientific contributions made by
Dr Kenzo Kaneko and Myrna B Dolovich, and their
friendship.
of ventilation, the presence of regional differences in DPr
could profoundly affect all measurements of lung mechanics
based on the determination of DPr in a circumscribed area of
the lung. In fact, most lung mechanics measurements are
performed with the esophageal balloon technique that involves determination of local pressure (8). If DPr is not uniform, measurements of pulmonary flow resistance and
dynamic lung compliance are questionable because the local
changes in Pr, which are measured via the esophageal balloon, may not reflect the ‘overall’ (average) change in pressure over the whole lung surface (18). However, there is
evidence that suggests that in normal humans, under most
physiological conditions, the changes in Pr are relatively
uniform (22). In this study, the changes in mouth pressure
during a spontaneous inspiration against a closed tap were
compared with those in esophageal pressure. While in sitting and lateral postures, the changes in esophageal and
mouth pressure were relatively close. While in the supine
position in the same instance, the DP at the mouth differed
substantially from that in the esophagus. Because in the
above experiments the changes in occluded mouth pressure
reflected the ‘overall’ changes in pressure over the whole
lung surface, the concordance between local (esophageal)
DP and overall (mouth) DP suggests that in spontaneously
breathing subjects the changes of pleural pressure are relatively uniform, at least in sitting and lateral decubitus positions. It should be noted, however, that even small regional
differences in DPr may influence the regional distribution of
ventilation and contribute to sequential lung emptying at
lung volumes greater than FRC (4). More marked nonuniform changes in DPr, sufficient to cause substantial changes
in regional distribution of gas, can be achieved by selective
voluntary contraction of different respiratory muscles, as
first demonstrated by Roussos et al (23).
There is virtually no information concerning regional
flow resistance. Regional differences in bronchomotor
tone, viscoelastic behaviour and other factors inherent in
the complex geometry and aerodynamics of the airways
may well cause substantial regional differences in flow resistance. Clearly, further studies are needed to resolve this
topic, which must play an important role in distribution of
ventilation, particularly during muscular exercise.
Since the early work of Robertson et al (24), it has been
amply shown that the regional distribution of gas changes
with increasing flow rates (4,19). This point was further explored by Pedley et al (25), whose model predictions were in
general qualitative agreement with the experimental results.
However, there are not yet any systematic studies of the regional distribution of ventilation during exercise.
Clearly, further work is needed before the factors determining the static dynamic distributions of gas within different regions of the lungs are fully understood. Nevertheless,
the present knowledge has provided useful information to explain the abnormalities in regional distribution of ventilation
and gas exchange in a variety of pulmonary and cardiac disorders.
Finally, it should be noted that during normal tidal breath-
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ACKNOWLEDGEMENT: I wish to thank Angie Bentivegna for
typing this manuscript.
REFERENCES
1. Milic-Emili J, Henderson JA, Dolovich MB, Trop D, Kaneko K.
Regional distribution of inspired gas in the lung. J Appl Physiol
1966;21:749-59.
2. Garfield E. Most-cited articles in the 1960s. Clinical research.
Current Contents 1980;6:5-14.
3. West JB. Regional differences in the lung. New York: Academic
Press, 1977.
4. Milic-Emili J. Topographical inequality of ventilation. In: Crystal RG,
West JB, Weibel ER, et al eds. The Lung. Philadelphia : Raven
Publishers, 1997:1415-23.
5. Garfield E. The 1,000 most-cited contemporary authors. Current
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6. Petit JM, Milic-Emili G. Measurement of esophageal pressure.
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7. Milic-Emili J, Mead J, Turner JM, Glauser EM. Improved technique
for estimating pleural pressure from esophageal balloons. J Appl
Physiol 1964;19:207-11.
8. Milic-Emili J, Mead J, Turner JM. Topography of esophageal pressure
as a function of posture in man. J Appl Physiol 1964;19:212-6.
9. Kruger JJ, Bain T, Patterson JL Jr. Elevation gradient of intathoracic
pressure. J Appl Physiol 1961;16:465-8.
10. Frank NR. A comparison of static volume-pressure relations of
excised pulmonary lobes of dogs. J Appl Physiol 1963;18:274-8.
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pulmonary function studied with xenon133. J Clin Invest
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12. Anthonisen NR, Milic-Emili J. Distribution of pulmonary
perfusion in erect man. J Appl Physiol 1966;21:760-6.
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Bates DV. Regional distribution of ventilation and perfusion as a
function of body position. J Appl Physiol 1966;21:767-77.
14. Bryan AC, Milic-Emili J, Pengelly LD. Effect of gravity in
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16. Rahn H, Fenn WO. A graphical analysis of respiratory gas exchange;
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characteristics of excised human lungs. Thorax 1981;36:290-5.
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Imhomogeneity of pulmonary ventilation during sustained
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Roussos CS, Fixely M, Genest J, et al. Voluntary factors influencing
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Robertson PC, Anthonisen NR, Ross D. Effect of inspiratory flow on
regional distribution of inspired gas. J Appl Physiol 1969;26:438-43.
Pedley T, Sudlow JMG, Milic-Emili J. A nonlinear theory of the
distribution of pulmonary ventilation. Respir Physiol 1972;15:1-38.
Prisk GK, Guy HJ, Elliott AR, Paiva M, West JB. Ventilatory
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